Abstract
Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.
Highlights
The opioid system consists of three classical opioid receptors—termed μ (MOR), δ (DOR), and κ (KOR)—a non-classical nociceptin receptor (NOR), and endogenous opioid peptides
These studies were continued by Zielińska M et al [63], who characterized the effect of biphalin on mouse intestinal contractility in vitro and GI motility in vivo in animal models mimicking symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D)
Their studies showed that biphalin at a 1 μM concentration increased the number of cells passing through the membrane in a transwell migration assay and increased wound closure in a scratch assay, even though it did not stimulate the proliferation of human corneal epithelial cells (HCECs)
Summary
The opioid system consists of three classical opioid receptors—termed μ (MOR), δ (DOR), and κ (KOR)—a non-classical nociceptin receptor (NOR), and endogenous opioid peptides (dynorphins, enkephalins, endorphins, and endomorphins). Opioid receptors are expressed in various cells in both neuronal and non-neuronal tissues, including neuroendocrine, immune, and ectodermal cells [2]. Opioid peptides and their receptors play an important role in many physiological functions: mainly pain and analgesia, and stress and social status; tolerance and dependence; mental illness and mood; general activity and locomotion; gastrointestinal, renal, and hepatic function; cardiovascular responses; respiration and thermoregulation; immunological responses; seizures and neurological disorders; electrical-related activity and neurophysiology; and others [3]. In the course of extensive research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may potentially participate in the regulation of other opioid-dependent functions. Biphalin as a non-selective ligand of opioid receptors was studied as an antiproliferative, antiviral, immunomodulatory, neuroprotective, wound healing-improving, hypotensive, antioxidative, respiratory agent (Figure 1)
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